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Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 15344

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Dr. Tao Liu

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Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
Interests: natural product; drug discovery; pharmacology; biochemical engineering; purification; mass spectrometry; fatty acid; collagen
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Dr. Clementina Manera

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Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: cannabinoid research; allosteric/bitopic modulation; natural products; antioxidants; neurodegeneration
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Dr. Francesca Gado

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Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
Interests: medicinal chemistry; drug synthesis; drug discovery; organic synthesis; endocannabinoid system modulators synthesis; polyphenols
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Special Issue Information

Dear Colleagues,

Bioactive compounds from natural sources and related structural analogues are attracting particular attention for their possible therapeutic potential and medical applications, especially for cancer, cardiovascular diseases, and infectious diseases. Nevertheless, bioactive compounds from complex matrix sources also present a great challenge to discovery, isolation, characterization, evaluation, and application. Improved isolation techniques, analytical tools, genome mining, engineering strategies, and microbial culturing advances are addressing such challenges and opening up new opportunities. The aim of this Special Issue is to collect important contributions in the field of bioactive compounds from plants, microbes, and animals. It covers research topics, including the following:

The isolation, structural elucidation, synthesis, transformation, and chemical modification of bioactive compounds.
Applications of advanced analytical technologies to bioactive compounds, including NMR, LC-MS, HRMS, IR, microcrystal electron diffraction, metabolomics, the profiling of responses to bioactive molecules at the single-cell level, genome-mining-driven discovery of bioactive compounds and related structural analogues, and the application of advanced microbial culturing approaches to identify new bioactive compounds.
The potential therapeutic applications and mechanisms of natural and natural-derived bioactive compounds based on in vitro or in vivo experiments.

We encourage you to send research and review articles related to aspects relevant to this Special Issue topic. Bioactive evaluations of crude extracts are acceptable only as supporting data for pure isolates with well-characterized structures.

Dr. Tao Liu
Dr. Clementina Manera
Dr. Francesca Gado
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

bioactive compound
natural product
isolation
synthesis
structural elucidation
bioactivity evaluation

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Related Special Issue

Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications in Molecules (11 articles)

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Research

33 pages, 4347 KB

Open AccessArticle

Encapsulation of Plant Extracts in a Psyllium/Starch Matrix: Synthesis and Functional Properties

by Magdalena Krystyjan, Gohar Khachatryan, Karen Khachatryan, Robert Socha, Anna Lenart-Boroń, Mariusz Witczak, Marcel Krzan, Anna Areczuk and Martyna Waśko

Molecules 2026, 31(6), 1026; https://doi.org/10.3390/molecules31061026 - 19 Mar 2026

Viewed by 259

Abstract

This work presents a method to encapsulate plant extracts within a binary polysaccharide carrier and to characterize the physicochemical and rheological performance of the resulting biocomposites in the context of food use. Using a starch/psyllium matrix, extracts from Sambucus nigra (SN), Aronia melanocarpa (AM), and Echinacea purpurea (EP) were effectively protected and incorporated through a stepwise workflow encompassing matrix preparation, encapsulation, structural verification, and functional assessment. SEM revealed a porous network containing uniformly distributed, extract-loaded spherical structures (~800–1500 nm), while FTIR supported the presence of hydrogen bonding and hydrophobic interactions that contributed to system stability. The prepared nanoemulsions showed shear-thinning (pseudoplastic) behavior, indicating favorable processing characteristics, whereas most physicochemical and bioactivity measurements were performed on lyophilized composites. The dried materials preserved extract-specific color signatures (ΔE > 5) and exhibited distinct thermal responses: AM produced a pronounced plasticizing effect (Tg reduced by >20 °C), while the incorporation of extracts generally delayed thermal degradation, consistent with polyphenol–starch interactions. Phase-transition behavior was also altered, with melting peaks suppressed for SN and AM and melting temperatures lowered for EP. Surface analysis indicated increased hydrophobicity and a reduced polar component of surface free energy, suggesting improved moisture barrier potential. Antioxidant capacity closely tracked total phenolic content (r > 0.94), with caffeic acid contributing strongly, particularly in EP-based systems. Antimicrobial activity depended on extract type (broad-spectrum for EP, selective for SN, minimal for AM), and the comparatively higher sensitivity of Gram-negative bacteria points to improved phenolic availability and membrane interactions upon encapsulation. Collectively, these results highlight the starch/psyllium matrix as a flexible platform for stabilizing plant extracts while enabling tunable functional attributes for functional food applications. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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21 pages, 1784 KB

Open AccessArticle

Microencapsulation of Phenolic Extracts from Verbascum sinaiticum Leaf Using Maltodextrin and Gum Arabic: Physicochemical Properties, Encapsulation Efficiency, and Storage Stability

by Alemu Belay Legesse, Shimelis Admassu Emire, Timilehin Martins Oyinloye and Won Byong Yoon

Molecules 2026, 31(3), 471; https://doi.org/10.3390/molecules31030471 - 29 Jan 2026

Viewed by 529

Abstract

Verbascum sinaiticum (V. sinaiticum), locally known as “Qetetina” in Ethiopia, is a rich source of phenolic compounds, but its stability and sensory limitations restrict its application. This study evaluated the physicochemical, functional, morphological, structural, storage stability, and in vitro digestibility characteristics of V. sinaiticum extract encapsulated with 100% Gum Arabic (GA), 100% maltodextrin (MD), and a mixed coating material (MD:GA = 8:2 ratio) using freeze-drying. MD-based microcapsules demonstrated superior functional properties, including high water solubility (98.48%), low moisture content (1.36%), low hygroscopicity (14.61%), and high encapsulation efficiency (81.31%). During 32 days of storage, MD microcapsules retained 71.84% of total phenolic content and showed minimal release under gastric and thermal conditions, while GA encapsulates were less stable. Structural analysis using XRD, FTIR, and SEM confirmed successful encapsulation, with compact morphology, consistent phenolic preservation, and structural integrity. Furthermore, encapsulation masked the undesirable sensory attributes of the extract, enhancing its potential use in nutraceuticals. Overall, freeze-drying with MD provided the most effective encapsulation system, significantly improving the stability and storage potential of V. sinaiticum extract. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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28 pages, 2875 KB

Open AccessArticle

Chemical Profiling and Cheminformatic Insights into Piper Essential Oils as Sustainable Antimicrobial Agents Against Pathogens of Cocoa Crops

by Diannefair Duarte, Marcial Fuentes-Estrada, Yorladys Martínez Aroca, Paloma Sendoya-Gutiérrez, Manuel I. Osorio, Osvaldo Yáñez, Carlos Areche, Elena Stashenko and Olimpo García-Beltrán

Molecules 2026, 31(2), 326; https://doi.org/10.3390/molecules31020326 - 17 Jan 2026

Viewed by 477

Abstract

This study evaluates the chemical profile and antifungal efficacy of essential oils from Piper glabratum, Piper friedrichsthalii, and Piper cumanense against the cocoa pathogens Moniliophthora roreri and Phytophthora palmivora. Microwave-assisted hydrodistillation followed by GC-MS analysis identified 80 constituents, predominantly monoterpenes and sesquiterpenes, which exhibited significant mycelial inhibition comparable to commercial fungicides. Beyond basic characterization, a comprehensive chemoinformatic analysis was conducted to elucidate the molecular mechanisms driving this bioactivity. The computed physicochemical landscape reveals a dominant lipophilic profile (average LogP 3.4) and low polarity (TPSA 11.5 Å²), characteristics essential for effective fungal membrane penetration. Structural mining identified conserved benzene and cyclohexene scaffolds alongside specific 1,3-benzodioxole moieties, while Maximum Common Substructure (MCS) analysis uncovered high similarity clusters among phenylpropanoids and sesquiterpenes. These findings suggest a synergistic mode of action where conserved structural backbones and interchangeable diastereomers facilitate membrane destabilization and ion leakage. Consequently, the integrative chemoinformatic profiling elucidates the molecular basis of this efficacy, positioning these Piper essential oils not merely as empirical alternatives, but as sources of rationally defined synergistic scaffolds for next-generation sustainable fungicides. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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34 pages, 1006 KB

Open AccessArticle

Design, Synthesis, and Antitumor Biological Evaluation of Galaxamide and Its Analogs

by Yanyan Guo, Huixia Fan, Zhiqiang Luo, Jian Yang and Guodu Liu

Molecules 2025, 30(11), 2362; https://doi.org/10.3390/molecules30112362 - 29 May 2025

Viewed by 1071

Abstract

Galaxamide, an N-methylated cyclo-pentapeptide containing five D-leucines isolated from Galaxaura filamentosa, has shown significant antitumor activity. This unique cyclo-pentapeptide offered a fresh skeleton for structural modifications. Herein, galaxamide and its 23 analogs (Gala01~Gala24) were designed and synthesized by substituting D-leucine with various proteinogenic amino acids or altering the amino acid configuration using the “3 + 2” strategy, and the in vitro antitumor activity of these cyclopeptides was studied utilizing the CCK-8 assay against two human tumor cell lines (A549 and K562) and one human normal cell line (293T). The total yields of galaxamide and its analogs reached 9.7% and 9.1–16.0%, respectively. CCK-8 assays demonstrated that these compounds showed broad-spectrum antitumor activity, with Gala04 exhibiting outstanding activity against K562 cells (IC₅₀ = 4.2 µM). The anticancer efficacy of galaxamide analogs against tumor cell lines was significantly influenced by the quantity of D-leucines and the D-leucine position. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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20 pages, 3758 KB

Open AccessArticle

Study of Natural Dyes’ Liposomal Encapsulation in Food Dispersion Model Systems via High-Pressure Homogenization

by Lubomír Lapčík, Barbora Lapčíková, Tomáš Valenta, Martin Vašina, Pavlína Dudová and Miroslav Fišera

Molecules 2025, 30(8), 1845; https://doi.org/10.3390/molecules30081845 - 20 Apr 2025

Cited by 1 | Viewed by 2046

Abstract

The aim of this study was to investigate the encapsulation of natural food dyes incorporated into liposomes in terms of particle size, rheological and colour properties, zeta potential, and encapsulation efficiency. The liposomes contained dye substances of anthocyanins from freeze-dried raspberry powder (R), copper complexes of chlorophyllins (C), or commercial-grade β-carotene (B). The phospholipid envelope was composed of sunflower lecithin and carboxymethylcellulose sodium salt as a surface stabilizer treated by high-pressure homogenization. The median particle diameter of R and C systems fluctuated around 200 nm, while B systems showed a broader range of 165–405 nm. The rheological results demonstrated a specific flow behaviour pattern dependent on the rotational shear applied, indicating a flow-induced structural change in the dispersions. Samples were characterized by a translucent profile with relatively high lightness, accompanied by a hue angle (h*) typical of the dye encapsulated. The zeta potential was approx. −30 mV, showing electrokinetically stabilized dispersions. The encapsulation efficiency (EE) varied significantly, with the highest EE observed for anthocyanins, ranging from 36.17 to 84.61%. The chlorophyll encapsulation was the least effective, determined in the range between 1.82 and 16.03%. Based on the suitability index, optimal liposomal formulations were evaluated by means of the Central Composite Design (CCD). Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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14 pages, 4393 KB

Open AccessArticle

Structural Characterization of Polysaccharides from Noni (Morinda citrifolia L.) Juice and Their Preventive Effect on Oxidative Stress Activity

by Bin Zhang, Xiaoyu Wei, Peiwen Du, Huangqun Luo, Lanfang Hu, Liping Guan and Guangying Chen

Molecules 2025, 30(5), 1103; https://doi.org/10.3390/molecules30051103 - 27 Feb 2025

Cited by 4 | Viewed by 1858

Abstract

Polysaccharides are very promising molecules in the field of pharmacotherapy. Knowing this, the aim of this study was to extract, characterize, and evaluate the action of the polysaccharides in noni juice, using biological models of Type 2 diabetes mellitus processes. In this study, one polysaccharide named NJSPd−1 was separated from fermented noni fruit juice. The characterization assay showed that NJSPd−1 had a molecular weight (Mw) of 18,545 Da. NJSPd−1 consisted of galacturonic acid, galactose, rhamnose, and arabinose, with a molar ratio of 28.79:20.34:19.80:18.84 according to HPGPC analysis, and the glycosidic bond mainly included →4)-α-D-GalAp-(1→, 4)-β-D-Glcp-(1→, →2)-α-L-Rhap-(1→, and →3)-α-L-Araf-(1→. The prevention of oxidative stress activities by NJSPd−1 was evaluated using high-glucose-induced oxidative stress in HepG2 cells. In vitro results showed that NJSPd−1 influenced the downregulation of the proteins and genes Nrf2, Keap1, HO-1, and NQO1 in HepG2 cells. These results suggest that NJSPd−1 exerted a protective effect against oxidative stress in HepG2 cells by activating the Nrf2/HO-1/NQO1 signaling pathway. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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15 pages, 2181 KB

Open AccessArticle

Characterization and Otoprotective Effects of Polysaccharides from Arthrospira platensis

by Matteo Banti, Mercedes Garcia-Gil, Lorenzo Guidotti, Graziano Di Giuseppe, Simona Rapposelli, Daniela Monti, Silvia Tampucci, Marinella De Leo, Francesca Gado, Paola Nieri and Clementina Manera

Molecules 2025, 30(2), 224; https://doi.org/10.3390/molecules30020224 - 8 Jan 2025

Cited by 4 | Viewed by 1999

Abstract

Hearing loss is one of the most common sensory disorders in humans, and a large number of cases are due to ear cell damage caused by ototoxic drugs including anticancer agents, such as cisplatin. The recent literature reported that hearing loss is promoted by an excessive generation of reactive oxygen species (ROS) in cochlea cells, which causes oxidative stress. Recently, polysaccharides from the cyanobacterium Arthrospira platensis showed many biological activities, including antioxidant activity, suggesting their potential use to combat hearing loss. On these bases, this study describes the extraction, purification, and characterization of water-soluble polysaccharides from A. platensis (SPPs) and the investigation of their protective role against cisplatin toxicity on House Ear Institute-Organ of Corti (HEI-OC1) cells. The results showed that SPPs (5–80 µg/mL) induced a dose-dependent increase in viability, statistically significant at 40 µg/mL and 80 µg/mL. Moreover, SPPs, evaluated at 80 µg/mL, inhibited the cisplatin-induced ROS level increase in HEI-OC1. This evidence highlights the potential of SPPs as natural candidates to protect cochlear ear cells against ototoxic oxidative agents. Moreover, in view of the potential use of microalgal polysaccharides to realize hydrogels, SPPs could also represent a healthy carrier for other topically administered otoprotective agents. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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10 pages, 4785 KB

Open AccessArticle

Dereplication of Natural Product Antifungals via Liquid Chromatography–Tandem Mass Spectrometry and Chemical Genomics

by Nathaniel J. Brittin, David J. Aceti, Doug R. Braun, Josephine M. Anderson, Spencer S. Ericksen, Scott R. Rajski, Cameron R. Currie, David R. Andes and Tim S. Bugni

Molecules 2025, 30(1), 77; https://doi.org/10.3390/molecules30010077 - 28 Dec 2024

Viewed by 2757

Abstract

Recently expanded reports of multidrug-resistant fungal infections underscore the need to develop new and more efficient methods for antifungal drug discovery. A ubiquitous problem in natural product drug discovery campaigns is the rediscovery of known compounds or their relatives; accordingly, we have integrated Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) for structural dereplication and Yeast Chemical Genomics for bioprocess evaluation into a screening platform to identify such compounds early in the screening process. We identified 450 fractions inhibiting Candida albicans and the resistant strains of C. auris and C. glabrata among more than 40,000 natural product fractions. LC-MS/MS and chemical genomics were then used to identify those with known chemistry and mechanisms of action. The parallel deployment of these orthogonal methods improved the detection of unwanted compound classes over the methods applied individually. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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30 pages, 4917 KB

Open AccessArticle

Polyphenolic Compounds in the Stems of Raspberry (Rubus idaeus) Growing Wild and Cultivated

by Ain Raal, Anni Vahtra, Oleh Koshovyi, Tetiana Ilina, Alla Kovalyova and Tõnu Püssa

Molecules 2024, 29(21), 5016; https://doi.org/10.3390/molecules29215016 - 23 Oct 2024

Cited by 5 | Viewed by 3215

Abstract

The stems of Rubus idaeus L., a byproduct of the fruit–food industry, are known sources of bioactive compounds. The main objective of this study was to investigate the composition of polyphenolic compounds in R. idaeus stems. Seven cultivated raspberry varieties, thirteen garden samples, including five well-known raspberry varieties, and thirteen wild raspberry samples from different locations in Estonia were analyzed. The HPLC-MS method detected 62 substances, of which 42 were identified, 12 were tentatively identified, and 8 compounds remained unknown. Protocatechuic acid pentoside was dominant in most varieties and in all garden and wild raspberry samples. Dihydroxybenzoic acid hexoside 1, p-coumaroyl quinic acid 1, quercetin 4’-glucuronide, and p-coumaric acid glycoside were found in significant quantities. Correlations among the contents of individual compounds were established. When studying the dynamics of polyphenolic compound accumulation in, for example, the GR1 sample over a year, it was found that, in raspberry stems, the largest amount of them accumulated in April and slightly less in January and October. Investigating the dependence of the accumulation of polyphenols on the parts of the stem, it was found that the upper parts have the highest phenolic contents. Therefore, it is recommended to harvest approximately the upper third of the stem. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications, 2nd Edition)

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